Tuesday, September 25, 2012

I missed this, when it was published back in May, but luckily Kelly Close (of Close Concerns, who publishes DiaTribe) reported on it:

At 1 year, intravenous infusions of Prochymal were reportedly well tolerated, with no differences in adverse event rates between the Prochymal and placebo groups.

With regard to efficacy, no significant differences in stimulated C-peptide levels were observed between the two arms (the primary efficacy endpoint), although a trend towards fewer hypoglycemic events in the Prochymal arm was observed.

A full analysis will be performed following an additional year of follow-up (for a total of 24 months)

My translation is this:

The trial failed its primary endpoint.

The researchers are trying to be optimistic about a small, vague result in one of the secondary endpoints.

The study will get more data after another year, and they are hoping for better news.

DiaTribe is a free on line newsletter (http://www.diatribe.us/), which is is a great source of info on diabetes research, technology, etc.

NI-0401 by NovImmune Failed a Long Time Ago

Years ago a company called NovImmune started a phase-II trial for their drug NI-0401 aimed at type-1 diabetes. After that, no news. This drug was targeted at CD3, and all the other CD3 drugs failed, so I always assumed this one had, as well. But there never was any news, and I never saw an official announcement. However, NovImmune updated their entire web site, and NI-0401 is still there, but diabetes is not listed as a target at all. Also, I found a European clinical trial registry, which showed that the long ago study had been canceled just months after it started.

This is the only treatment that I'm following that is currently in phase-III trials. The results from previous work suggest it might be a "longer, strong honeymoon" type treatment, rather than a cure. they have already finished one phase-III trial, and this is their second. The FDA requires two, so when this one completes, if it is successful, they will be ready to move into "marketing approval" phase, which takes a year or two.

Why is this important? For two reasons. First, because it is now possible to predict when they will finish collecting data. (Since this study gathers data for 2 years, it will finish about Sept 2014.) Second, because much of the uncertainty that surrounds clinical trials, is involved with recruiting participants. It is often unclear how hard it will be to recruit people, and long it will take. But that this point, all that cunertainty is behind the researchers. From now on, it is just gather data, then analyze data, and then publish data. Researchers have a lot more control over those later stages, then over recruiting people in the first place.

This was a very interesting study of doctors. Basically, the researchers gave doctors summaries of research results. These summaries breifly described a study's results, methodology, and source of funding. The doctor was then asked questions to determine how much they trusted the results, and how willing they were to proscribe the medicine being tested, based on the trial. (The research described was fictional, so the doctors did not have any prior knowledge of the drugs in question.)

Here is a summary of the results:

The study found that physicians weighted their assessment of the rigor of a trial based on pharma funding, and that they were half as willing to prescribe those disclosing industry sponsorship as they were those disclosing NIH funding, regardless of methodological rigor.

Discussion
I think these results are good in two separate (but related) ways. First, they suggest to me that doctors properly "discount" clinical trials funded by industry. Second, it suggests to me that when a doctor recommends a treatment, they are already taking into account who funded the studies suggesting its use. The recent problems with pharma PR guys "ghost writing" research articles, and withholding placebos from some researchers has made some people nervous about the accuracy of studies they do fund. I think it is proper that doctors are also nervous, and I feel good that the average doctor in the study took into account the funding source of clinical trials they read about.

Interestingly, the researchers who ran this particular trial are a little unhappy about their own results. They seem to think that when comparing two studies, if the methodologies are equally rigorous, that the results should be weighted the same, no matter who did the funding. They are specifically worried about doctors undervaluing what the researchers consider large scale, well designed, industry funded studies. I disagree. I think the prescribing doctors are doing the right thing by undervaluing (or "discounting") equally rigorous studies that are funded by industry. I view the attitude of these researchers as being very "old school" (and in this case, out of date). Sure, in the 1950s the idea was that rigorous trial methodology and peer review together were all that was needed to ensure accurate results. The idea was that the scientific method was so good that who funded the trial was not critical to the quality of the results. But 60 years later, I don't think that's the consensus opinion. Now we know that quality starts with good methodology and peer review, but those alone are not enough.

Not for a cure, but of interest, are the results of two studies testing symlin in type-1 diabetics. Only one was placebo controled, and it found:

analysis of 248 patients from a 29-week, placebo-controlled study, measurements in the normal range based on ADA criteria increased from 37.3 percent to 43.9 percent for SYMLIN-treated patients (n=115), compared to an increase from 38.2 percent to 40.9 percent in those receiving placebo (n=133). The percent of measurements in the normal range based on AACE criteria increased from 22.6 percent to 27.8 percent for SYMLIN-treated patients compared to an increase from 24.1 to 25.0 in those receiving placebo. The percentage of readings in the hypoglycemic range remained relatively stable.

Discussion

I'm not sure I'd take a second injection with meals (or a first injection for pump users) for that level of improvement, but it's still interesting. I also think that A1c improvements would be a better measure of goodness than % inside of guidelines. But you gotta start somewhere.

Maybe we'll end up with a tri-treatment artificial pancreas. It will dose insulin for highs, glucagon for lows, and symlin with meal boluses.

Tuesday, September 11, 2012

In the US, we are starting the "Walking Season" when JDRF asks us to walk to raise money for cure. So I'd like to do my part, by reminding you all how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 63% of the treatments currently in human trials have been funded by JDRF. (And the number is 66% for the later phase trials) This is an strong impact; one that any non-profit should be proud of.

This summary does not include Artificial Pancreas research or stem cell trials, which I discuss separately. The list is a list of treatments, not a list of trials. For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are testing the same treatment, it is only one item in the list. DiaPep277 is running several trials, Rituximab has two, and so on. Finally, those treatments marked "(Established)" have at least one trial which is open to people who have had type-1 diabetes for over a year. So those are open to non-honeymoon diabetics.

Also remember that I give an organization credit for funding a treatment if they funded it any any point in development; I don't limit it to the current trial. For example, JDRF is not funding the current trials for DiaPep277, but they did fund much of the early research into it, which allowed it to grow into human trials.

Cures in Phase-III Human Trials
Summary: there is only one treatment in phase-III right now, and it has been funded by JDRF.

Andromedia's DiaPep227

This treatment has more than one study active right now.

Cures in Phase-II Human Trials
Summary: there are 14, and 9 of them have been funded by JDRF, either directly or indirectly through ITN. Here are the treatments that have been funded by JDRF:

Abatacept by Orban at Joslin Diabetes Center

Diabecell by Living Cell Technologies (Established)

Exsulin (previously INGAP) by Exsulin (Established)

Kineret / Anakinra by Mandrup-Poulsen at Steno Diabetes Center

Rituximab by Pescovitz at Indiana

Sitagliptin and Lansoprazole at Sanford Health

Thymoglobulin (also known as ATG) by Gitelman

Umbilical Cord Blood Infusion by Haller at University of Florida

Xoma 52 by Xoma Corp (Established)

Not funded by JDRF:

ATG and autotransplant by Burt, and also Snarski, and also Li

Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia

Brod at University of Texas-Health Science Center

Canakinumab by TrialNet

NI-0401 by NovImmune

Cures in Phase-I Human Trials
Summary: there are 23, and 14 of the are funded by JDRF and 9 are not. Here is the list funded by JDRF:

Alefacept by TrialNet

AAT or Alpha-1 antitrypsin by OmniBio and also Kamada

ATG and GCSF by Haller at University of Florida (Established)

BHT 3021 by Bayhill Theraputics (Established)

CGSF by Haller at University of Florida

Trucco at Children’s Hospital of Pittsburgh (Established)

IBC-VS01 by Orban at Joslin Diabetes Center

Leptin by Garg at University of Texas

Nasal insulin by Harrison at Melbourne Health

Polyclonal Tregs by Gitelman at University of California San Francisco

Pro insulin peptide by Dayan at Cardiff University

Proleukin and Rapamune by Greenbaum at Benaroya Research Institute (Established)

Lisofylline by DiaKine

Stem Cell Educator by Zhao (Established).

Not funded by JDRF:

BCG by Faustman at MGH (Established)

CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established)

Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine

GABA by Lunsford at the University of Alabama at Birmingham.

Monolayer Cellular Device (Established)

Rilonacept by White at University of Texas

The Sydney Project, Encapsulated Stem Cells (Established)

Pioglitazone by Wilson at Stony Brook

Summary of all Trials
38 in total
24 funded by JDRF
So 63 % of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 in total (34% of all trials)
8 funded by JDRF
So 62% of the trials recruiting established type-1 diabetics, are funded by JDRF.

Compared to Last Year
In 2011 there were 37 treatments in clinical trials, in 2012 there are 38 (growth of 3%)
In 2011 there was 1 treatments in Phase-III trials, in 2012 there is still 1 (no change).
In 2011 there were 16 treatments in Phase-II trials, in 2012 there are 13 (drop of 23%).
In 2011 there were 20 treatments in Phase-I trials, in 2012 there are 23 (growth of 13%).

In previous years I have included some drugs that were basically being tested as treatments (adjuncts to insulin that would give people better control or help them use less insulin). This year, I have removed those from the list. I included them before because there was always a chance they would lead to a cure. I'm now of the opinion that was wishful thinking, so I'm no longer including them here.How I Count Trials for This Comparison

I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.

I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.

For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.

The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.

I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.

Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.

I use the term "US Gov" for all the different branches and organizations within the United States of America's federal govenment (so includes NIDDK, NIAID, NICHD, etc.)

I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I'm an adviser to JDCA. I also own stock in several of the companies discussed here.

Friday, September 7, 2012

Several different groups are experimenting with using insulin to prevent or cure type-1 diabetes. This is similar to giving people with food allergies the food they are allergic to in tiny doses, gradually building up the dose over years until they are no longer allergic. Because insulin is basically a protein, it gets digested, so you can't take pills of insulin. Different groups are experimenting with different methods of getting insulin into a person, in the hopes that it will result in a cure.

This particular group is using a nasal spray. They want to enroll 120 people, and started back in 2006, but I've not previously blogged on it. They are now hoping to finish in late 2016. Obviously, it's been going on for a long time. Because it is being done in Australia (with it's lower population), I'm sure it is taking them longer than they would like to fully enroll it.

This is the other IL-2 clinical trial. It involves 25 people who have had type-1 for less than 2 years. It is complete, meaning they have gathered all the data needed, but have not yet published the results. Since they were complete in April, if they have a positive result, I would expect publication by April 2013, and if they have a neutral, negative, or hard to interpret result, publication after that.

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This blog discusses cures and preventatives for type-1 diabetes that are either in human trials or just about to start. Treatments for diabetes are not generally discussed here, unless they can turn into a cure or a preventative. My definition of a cure is this:1. Blood sugar control without testing and with doctor's visits 4 times a year, or less. Any cure must result in an average lifespan close to normal.2. Does not require a lifetime of immunsuppressive drugs, so it is not trading one treatment for another. (but a couple of operations, or a short course of drugs is OK)Obviously, this is my personal definition of a cure; yours may differ.Because a cure for type-1 diabetes is likely to involve a combination of several different drugs or treatments, I try to follow research into anything which may be an important part of the cure.

My Non-Conflict of Interest Statement

I don't work for a company involved in medical research; I never have.

I don't get paid in any way by any company doing medical research; I never have. And that includes free samples, free travel, or free anything. I do sometimes participate in market research studies or focus groups, and they sometimes pay.

None of the hours that I have put into my blog, or the posts that I make to any web site, has ever been paid for. (Except for some very nice and heart felt thank-you emails, and those are worth more than money.)

My daughter has type-1 diabetes and participates in clinical trials. I sometimes report on trials that she participates in, but I do not reveal her participation because I consider her medical history to be private.

I sometimes "beta test" new software or devices involved in type-1 diabetes. When I'm blogging about something where I have been given special access, I say so.

In the past I have volunteered with JDRF, The NIIB Project, and I currently am a fellow with JDCA. JDRF and NIIB Project was completely unpaid. JDCA has given me equipment that I use to help my blogging.

Over the years my daughter has used several types of insulin, several types of meters, and pumps made by different manufacturers. I don't always mention if I'm blogging about a company who's products she uses now or in the past (there are so many).